“What we have is a provocative set of findingsthat need to be replicated.” — PAOLA SEBASTIANICentenariansdistinguished byDNA signatures

By Tina Hesman Saey

People who live to be 100 often credit
their aging success to particular dietary
or lifestyle habits, religious faith or a
generally positive outlook. But scientists
have long believed extreme longevity
is at least partly in the genes.

Now a group of researchers has identified 281 genetic variants that together
distinguish people who live to be 105 or
more from everyone else with about
85 percent accuracy.

Further analysis reveals several
genetic signatures among centenarians, researchers led by Paola Sebastiani
and Thomas Perls of Boston University
report January 18 in the online journal
PLoS ONE. While the findings are drawing some criticism, the results suggest
that there is a genetic component to
extreme longevity.

Centenarians in the study have just
as many disease-associated genetic
variants as other people. So the researchers think that the inherited component
probably includes versions of genes that
protect against age-related diseases.

“What we have is a provocative set
of findings that need to be replicated,”
Sebastiani says.

In an earlier version of the work
that was published online in Science in
2010, she and the other Boston University researchers claimed to have found
a set of 150 genetic variants that could
correctly predict who would be a centenarian 77 percent of the time. But the
paper soon came under fire for technical
flaws. The researchers fixed the technical problem and engaged an independent lab at Yale University to analyze
the data.

Despite those revisions, the paper was
retracted from Science last year because
the journal said the results no longer
met standards for publication. Science’s
reasoning is disingenuous, says Nir
Barzilai, director of the Institute for
Aging Research at Albert Einstein
College of Medicine in New York City.
“The results, if anything, are stronger,”
he says. “The data are the data, and

No disease difference though 281 genetic variants can be used to distinguish centenarians from younger controls, few of those differences are due to a lack of disease-associated gene
variants. a look at 1,214 disease-associated locations in the genomes of 1,054 centenarians
and 4,118 controls found similar proportions of high-risk genetic variants in the groups.
sOurce: p. sebastiani ET AL/PLOS ONE 2012

it’s very striking.”But other geneticists have expressedvague unease with the findings.

“The obvious technical issues have
been corrected,” says geneticist Greg
Cooper of the HudsonAlpha Institute
for Biotechnology in Huntsville, Ala. But
longevity “is a messy trait” that may be
too complicated to explain with a small
number of genetic variants. “I’m not
totally sold,” Cooper says.

In the new study, the researchers
combed the genetic blueprints of 801
centenarians and 914 healthy younger
people for longevity-associated variants. The researchers also replicated the
findings with two additional rounds of
testing, first with a separate group of
253 people in their 90s and 100s and a
control group of 341 younger people,
then with a third set of 60 centenarians
and 2,863 other people.

The researchers detected only one
variant, linked to the Alzheimer’s
disease–associated APOE gene, that
met statistical standards for separating
supercentenarians from people with
a more average life span. Many other
variants also looked as if they might
be tied to longevity, but none passed
statistical muster.

So Sebastiani and her team began summing the effects of variants that didn’t
quite rise to the statistical threshold to
see if those individual differences added
up to a genetic signature that could predict longevity. As the researchers added
in more and more variants, up to the
281 reported in the study, their power to
predict centenarians increased.

Such grouping of genetic variants has
been used to study characteristics such
as height, body mass and intelligence.
That type of analysis may help detect an
underlying genetic component to a trait,
but it doesn’t indicate which biological
processes are important, says Elizabeth
Cirulli, a geneticist at Duke University’s
Center for Human Genome Variation.